Researchers found 1 million variants in the exomes of more than 6700 individuals, but most, it turns out, have little effect on complex traits.

Many researchers believe that rare genetic variants in humans might affect
complex traits like lipoprotein levels, but that might not necessarily be
the case at all. At this year’s American Society of Human Genetics meeting
in San Francisco, CA, a team of scientists reported that most rare variants
that they identified in a study of more than 67000 exomes have a weaker
effect on complex traits than they had expected.

As part of the National Heart, Lung and Blood Institute’s (NHLBI) Exome
Sequencing Project, the group sequenced the exomes from 4420
European-Americans and 2312 African-Americans. The researchers found about
1.2 million variants, 1.1 million of which they classified as rare. Some of
these variants were so rare that they only occurred in a single individual
enrolled in the study.

Although roughly 720,000 of these variants affected the resulting protein
sequence, the team could only link a few of these variants to disease
pathways. For example, the researchers found an association between a
variant in the Apoc3 gene with lower triglyceride levels.

“There’s a big learning curve, and we’re just learning to analyze this data,”
said team member Suzanne M. Leal, a professor of molecular and human
genetics at Baylor College of Medicine and director of the college’s Center
for Statistical Genetics.

Subjects were recruited from existing NHLBI studies, including the Jackson
Heart Study, the Atherosclerosis Risk in Communities Study, and the Women’s
Health Initiative. The team selected subjects based on disease phenotypes
that they were interested in, like high- or low-lipid levels, extreme blood
pressure, or early onset heart attacks. In all, the researchers analyzed
more than 80 heart, lung, and blood phenotypes.

In contrast to genome-wide association studies that identify
disease-associated variants scattered throughout the genome, this project
only looked at protein-coding regions of the genome. Leal and her colleagues
believe that this targeted approach has more potential to identify genetic
links to disease.

Most of the variations were found in specific populations. For example, Darc
gene variants were associated with varying white blood cell counts in
African-Americans, while variants in the F7 gene appeared to
influence levels of factor VII—a cog in the coagulation cascade—in
European-Americans.

The study also confirmed some previously known associations, such as high
levels of low-density lipoprotein—aka bad cholesterol—that track with
certain variants of the apoB gene, and associations between LepR
gene variants and levels of C-reactive protein, that increases the
body's response to inflammation.

“One thing we saw was that the effect sizes (of rare variants) aren’t as great
as many people predicted, so you need quite large sample sizes (to detect
associations),” said Leal.

In some cases, the project provided leads that the researchers are now
pursuing in follow-up studies. In these satellite studies, the researchers
employed an exome chip—which was developed with direct input from the exome
project—to analyze 240,000 coding variants.